The purpose of this study was to delineate the patient and surgical factors that contribute to the development of corneal neovascularization (CNV) after penetrating keratoplasty (PK). Thirty-six eyes of 36 patients with no antecedent CNV were enrolled in the study. Grafts were sutured to the host with 16 10-0 nylon sutures with the knots buried alternately in either the host or donor corneal stroma. Multiple perioperative factors were recorded for each patient, and at each postoperative visit systematic corneal drawings were used to follow the development of neovascularization. The stroma adjacent to each suture of each graft was given a neovascularization score based on the extent of vessel growth toward the wound interface. Univariate and multivariate analyses were performed, including generalized estimating equations logistic regression where each eye is considered a cluster of observations. Thirty-four patients without preoperative CNV or inflammation were followed prospectively for 6-9 (mean, 7) months after PK. Fourteen eyes (41%) developed some degree of CNV. Indication for keratoplasty, age, gender, phakic status, and size of donor button were not risk factors for CNV development. The most significant risk factor identified for any degree of CNV was placement of the suture knot in the host stroma (p = 0.00007), with the overall relative risk of CNV associated with these knots over 2 (95% confidence interval, 1.1-4.2). Furthermore, the mean recipient size in eyes with postoperative CNV was larger than eyes that did not develop neovascularization (p = 0.015), and active blepharitis was associated with a fivefold increase in the risk of developing CNV to the wound edge (p = 0.008). Embedding suture knots in the host stroma, active blepharitis, and a large recipient bed are significantly associated with postkeratoplasty CNV.